Inflammation Clinical Trial
— EPI-AirOfficial title:
Air Pollution, Epigenetics and Cardiovascular Health: A Human Intervention Trial
Verified date | May 2017 |
Source | Harvard School of Public Health |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
In this study, the pills formulated are being used to try to ameliorate the effect of air
pollution on epigenetic changes, specifically DNA methylation, potentially linked with
particulate matter air pollution inhalation and cardiovascular health effects. The way in
which this is achieved is that the vitamins, which act as methyl donors, add a methyl group
to the DNA to reverse the loss observed on exposure to air pollution.
Specifically for this study, the methyl donor supplement has been made by Jamieson
Laboratories, and consists of 50mg Vitamin B6 and 1 mg Vitamin B12, (both within Health
Canada approved limits) and 2.5 mg folic acid. The non-vitamin ingredients are those
commonly used in pill formation. However, the folic acid concentration is 2.5mg, which is
above the 1.0mg limit set by Health Canada for a natural health product. This concentration,
however, has been used in previous academic studies safely and effectively, and was also
formulated by Jamieson Laboratories. (ClinicalTrials.gov number, NCT00106886; Current
Controlled Trials number, ISRCTN14017017. HOPE2 study).
Status | Completed |
Enrollment | 10 |
Est. completion date | July 2014 |
Est. primary completion date | July 2014 |
Accepts healthy volunteers | Accepts Healthy Volunteers |
Gender | All |
Age group | 18 Years to 60 Years |
Eligibility |
Inclusion Criteria: - Healthy volunteer - Age 18-60 years old - Non-smoker - must be able to fast 8 hours prior to exposure visits and for a further 4 hours during the exposure Exclusion Criteria: - Subjects must not be regularly taking multivitamins, vitamins C & E, folate, medications, fish oil or aspirin, oral or inhaled steroids, for 4 weeks before and during the trial. - Lipid abnormalities - Asthma or respiratory disease - Hypertension (Bp> 140/90) or taking any blood pressure drug - Known cardiac disease - abnormal homocysteine or glucose levels |
Country | Name | City | State |
---|---|---|---|
Canada | Gage Occupational and Environmental Health St. Michael's Hospital/University of Toronto | Toronto | Ontario |
Lead Sponsor | Collaborator |
---|---|
Harvard School of Public Health | St. Michael's Hospital, Toronto, University of Toronto |
Canada,
Adar SD, Gold DR, Coull BA, Schwartz J, Stone PH, Suh H. Focused exposures to airborne traffic particles and heart rate variability in the elderly. Epidemiology. 2007 Jan;18(1):95-103. — View Citation
Baccarelli A, Cassano PA, Litonjua A, Park SK, Suh H, Sparrow D, Vokonas P, Schwartz J. Cardiac autonomic dysfunction: effects from particulate air pollution and protection by dietary methyl nutrients and metabolic polymorphisms. Circulation. 2008 Apr 8;117(14):1802-9. doi: 10.1161/CIRCULATIONAHA.107.726067. Epub 2008 Mar 31. — View Citation
Brook RD, Bard RL, Burnett RT, Shin HH, Vette A, Croghan C, Phillips M, Rodes C, Thornburg J, Williams R. Differences in blood pressure and vascular responses associated with ambient fine particulate matter exposures measured at the personal versus community level. Occup Environ Med. 2011 Mar;68(3):224-30. doi: 10.1136/oem.2009.053991. Epub 2010 Oct 8. — View Citation
Brook RD, Rajagopalan S, Pope CA 3rd, Brook JR, Bhatnagar A, Diez-Roux AV, Holguin F, Hong Y, Luepker RV, Mittleman MA, Peters A, Siscovick D, Smith SC Jr, Whitsel L, Kaufman JD; American Heart Association Council on Epidemiology and Prevention, Council on the Kidney in Cardiovascular Disease, and Council on Nutrition, Physical Activity and Metabolism.. Particulate matter air pollution and cardiovascular disease: An update to the scientific statement from the American Heart Association. Circulation. 2010 Jun 1;121(21):2331-78. doi: 10.1161/CIR.0b013e3181dbece1. Epub 2010 May 10. Review. — View Citation
Brook RD, Rajagopalan S. Particulate matter, air pollution, and blood pressure. J Am Soc Hypertens. 2009 Sep-Oct;3(5):332-50. doi: 10.1016/j.jash.2009.08.005. — View Citation
Liu L, Ruddy T, Dalipaj M, Poon R, Szyszkowicz M, You H, Dales RE, Wheeler AJ. Effects of indoor, outdoor, and personal exposure to particulate air pollution on cardiovascular physiology and systemic mediators in seniors. J Occup Environ Med. 2009 Sep;51(9):1088-98. doi: 10.1097/JOM.0b013e3181b35144. — View Citation
O'Neill MS, Veves A, Zanobetti A, Sarnat JA, Gold DR, Economides PA, Horton ES, Schwartz J. Diabetes enhances vulnerability to particulate air pollution-associated impairment in vascular reactivity and endothelial function. Circulation. 2005 Jun 7;111(22):2913-20. Epub 2005 May 31. — View Citation
O'Toole TE, Conklin DJ, Bhatnagar A. Environmental risk factors for heart disease. Rev Environ Health. 2008 Jul-Sep;23(3):167-202. Review. — View Citation
Zanobetti A, Canner MJ, Stone PH, Schwartz J, Sher D, Eagan-Bengston E, Gates KA, Hartley LH, Suh H, Gold DR. Ambient pollution and blood pressure in cardiac rehabilitation patients. Circulation. 2004 Oct 12;110(15):2184-9. Epub 2004 Oct 4. — View Citation
Zhong J, Karlsson O, Wang G, Li J, Guo Y, Lin X, Zemplenyi M, Sanchez-Guerra M, Trevisi L, Urch B, Speck M, Liang L, Coull BA, Koutrakis P, Silverman F, Gold DR, Wu T, Baccarelli AA. B vitamins attenuate the epigenetic effects of ambient fine particles in — View Citation
Zhong J, Trevisi L, Urch B, Lin X, Speck M, Coull BA, Liss G, Thompson A, Wu S, Wilson A, Koutrakis P, Silverman F, Gold DR, Baccarelli AA. B-vitamin Supplementation Mitigates Effects of Fine Particles on Cardiac Autonomic Dysfunction and Inflammation: A — View Citation
Zhong J, Urch B, Speck M, Coull BA, Koutrakis P, Thorne PS, Scott J, Liu L, Brook RD, Behbod B, Gibson H, Silverman F, Mittleman MA, Baccarelli AA, Gold DR. Endotoxin and ß-1,3-d-Glucan in Concentrated Ambient Particles Induce Rapid Increase in Blood Pres — View Citation
* Note: There are 12 references in all — Click here to view all references
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Other | mRNA expression of inflammatory genes (TNFa, TGFb, IFNg, IL17, IL2, IL6) in circulating T-helper lymphocytes; plasma cytokines. | We will extract total RNA from Th cells isolated and immediately preserved in mRNA later. We will design real-time PCR assays to measure mRNA levels of TNFa, IFN?, IL-17, TGFß, IL2 & IL6 following standardized procedures. All assays will be run in triplicates. We will measure 27 cytokines included in a pre-set Luminex Bio-Plex 27-plex panel. Analyses will include measures of the same mediators for which methylation analysis is measured (TNFa, IFN?, IL-17, TGFß, IL2, and IL6), which represent the strongest candidates for their roles in Th cells, as shown in cardiovascular models of hypertension. The remaining inflammatory mediators are IL7, IL8, IL12, GM-CSF, IL4, IL5, IL9, IL10, IL13, GM-CSF, IL1ß, IL1ra, IL15, IL17, MCP1, MIP1a, MIP1ß, PDGF-BB, VEGF, FGF, RANTES, IP-10, eotaxin, GCSF. Samples will be run in triplicates. Also, we will measure plasma CRP through a high-sensitivity method (Dade Behring). | 2 years | |
Primary | DNA methylation in circulating T-helper lymphocytes of six candidate genes (TNFa, TGFb, IFNg, IL17, IL2, IL6) | Blood will be collected from venous phlebotomy and processed for Th-cell isolation within 4hrs. DNA extraction will be performed manually on fresh unfrozen cells. DNA methylation analyses will be conducted using bisulfite-polymerase chain reaction-pyrosequencing. To select target sequences within each gene, we will rely both on assays from previous investigations and bioinformatic analysis using information from the genome browser on transcription factor binding sites conserved in the human/mouse/rat alignment, histone marks associated with active regulatory sequences and gene accessibility, and nucleosome occupancy. We will validate all assays using a titration curve of 0%-100% methylated DNA. Batch effect will be controlled by: a) using 0%, 50%, 100% methylation and universal DNA in each plate; b) running all samples from the same volunteer in one plate. We will intersperse 5% blind duplicates to test reproducibility. All samples will be assayed in duplicate runs. | 2 years | |
Secondary | Blood pressure (BP) , brachial artery diameter (BAD), endothelium-dependent flow-mediated dilation (ED-FMD) and heart rate variability (HRV). | BP will be measured at 30-min intervals during exposure using an automated oscillometric ambulatory monitor secured on the upper left arm. Three BP measures will be taken at each time point separated by 1 minute, and the mean of the 2nd and 3rd measures used. BAD, FMD and nitroglycerin-mediated dilatation will be measured using a Terason 2000 ultrasound with a 7.5-10.0 megahertz linear array transducer. Peak FMD within this period will be used as our primary study outcome for endothelial function. Continuous EKG monitoring will be performed using high-resolution digital 12-lead Holter monitors. Holter monitoring will take place for 24-hr periods which will include before (pre-exposure testing), during the 2-hr exposure and post exposure (just after and 24-hrs post). Immediately prior to exposure, after the exposure and 24 hrs later, we will collect 10-minute resting supine HRV readings. HRV will be evaluated on 5-min ECG data using standardized techniques. | 2 years |
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